EP2004173A2 - Utilisation d'aminaphtone pour la préparation d'un médicament destiné au traitement d'artériopathies - Google Patents

Utilisation d'aminaphtone pour la préparation d'un médicament destiné au traitement d'artériopathies

Info

Publication number
EP2004173A2
EP2004173A2 EP07734240A EP07734240A EP2004173A2 EP 2004173 A2 EP2004173 A2 EP 2004173A2 EP 07734240 A EP07734240 A EP 07734240A EP 07734240 A EP07734240 A EP 07734240A EP 2004173 A2 EP2004173 A2 EP 2004173A2
Authority
EP
European Patent Office
Prior art keywords
medicament
use according
aminapthone
aminaphtone
cells
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP07734240A
Other languages
German (de)
English (en)
Other versions
EP2004173B1 (fr
Inventor
Raffaella Scorza
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
Original Assignee
FONDAZIONE IRCCS ISTITUTO DI RICOVERO E CURA A CAR
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by FONDAZIONE IRCCS ISTITUTO DI RICOVERO E CURA A CAR filed Critical FONDAZIONE IRCCS ISTITUTO DI RICOVERO E CURA A CAR
Priority to EP11153882.3A priority Critical patent/EP2335695B1/fr
Publication of EP2004173A2 publication Critical patent/EP2004173A2/fr
Application granted granted Critical
Publication of EP2004173B1 publication Critical patent/EP2004173B1/fr
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the subject of the present invention is a novel use of the compound 2-hydroxy-3 -methyl-1, 4-napthohydroquino- ne-2-p-aminobenzoate, known by the common name a ' tni- naphtone (hereinafter defined, by simplicity, as aminapthone) , for the preparation of a medicament for treating arteriophaties; in particular, for the treatment, at the endothelial level, of arteriopathies of a degenerative inflammatory type.
  • a tni- naphtone hereinafter defined, by simplicity, as aminapthone
  • Aminaphtone is a compound having a known pharmacological activity and commercially available in Italy and other countries for many years; in Italy, for example, it constitutes the active substance of the CAPILLAREMA drug, a medicine of Laboratori Baldacci S.p.A., Pisa.
  • the drug is widely used 'in the symptomatic treatment of chronic venous failure of the lower limbs, a situation in which the hematic stasis affects the microcirculation by producing alterations of the structure arid the capillary functionality.
  • Pharmacological and clinical properties of this product have been published on scientific reviews and confirmed in these last years by the therapeutic use for the treatment of venous pathologies in countries where it is commercialized.
  • aminaphtone also has the ability of antagonizing pathological events referable to an • inflammatory state of the arterial vasal structure through different mechanisms than those currently known has never been shown.
  • the vascular • endothelium results to be a system, consisting of me- tabolically active cells and responsive to physiological stimuli. Said stimuli control in a meticulous way the blood flow, acting a complex role in the control of vasoreactivity> platelet aggregation and the resistance to thrombi formation.
  • endothelial cells synthesize and secrete components of the connective tissue and molecules with an antagonist ac- tivity therebetween.
  • the endothelial inflammation is at the basis of degenerative/inflammatory pathologies, with an evolutionary character, with the presence of vacuolization, loss of endothelial integrity, perivascular infiltration of lymphdcy-t ' SsV ' ⁇ macrophages, ' monocytes, fibroblasts, and increasing expression of adhesive molecules with the formation of a strong endogenous vasoconstrictor, such as endothelin, with a following hyperplasia of the in- tima, proliferation of smooth muscle cells of the vessels and a vascular remodelling.
  • a strong endogenous vasoconstrictor such as endothelin
  • statins drugs, which have however a double disadvantage: they are expensive therapies and determine, in an absolutely not negligible part of patients, a form of statin myopathy.
  • the object 'of the present invention is to provide an answer to the need above pointed out .
  • An object of the present invention is the use of aminapthone for the preparation of a drug for treating artheriopathies, as reported in the appended independent claim.
  • Figure 1 it graphically reports the inhibitory effect exerted by aminapthone, at different dosages, on the expression of the adhesive molecule E-selectine (ELAM- 1) from human endothelial cells ECV 304. Specifically, Fig.
  • FIG. 1 shows the density of membrane ELAM-I fluorescence, determined through cytofluorometric analysis (mean channel) in different samples of ECV 304 cells, in the following conditions, respectively: a.) in basal (Medium) and after a 48 hr incubation with basal medium additioned with aminapthone at a dosage of 4 mcg/ml (Amna) ; b.) after incubation/activation for 48 hr with IL-l ⁇ at 100 U/ml (IL-I) and, respectively, IL-I additioned with aminapthone (Amna) at concentrions of 2; 4; 5 mcg/ml . - .
  • Figure 2 it reports, in a block diagram, the inhibitory effect exerted by aminaphtone, at different dosages, on the endothelin production (ET-I) from human' endothelial cells ECV 304 incubated/activated with IL- l ⁇ .
  • Fig. 2 shows the, course of the ET-I production, dosed with a specific EIA-Kit, in different samples of ECV 304 activated with IL-l ⁇ alone at 100 U/ml (IL-I) and, respectively, with IL-I addi- tioned with aminapthone at concentrations of 2, 4, 6 racg/ml (A2 ; A4 ; A6) .
  • Figure 3 it reports, in a block diagram, the inhibitory effect exerted by aminaphtone, at different dosages, on the endothelin production (ET-I) from non- activated human endothelial cells ECV 304.
  • Fig. 3 shows the course of the ET-I production in different samples of ECV 304 non-activated with IL- l ⁇ but incubated with the culture medium (basal) alone and, respectively, with basal medium additioned with aminapthone at concentrations of 2 ; 4 ; 6 mcg/ml (A2 ; A4; A6) .
  • the present invention relates to the use of aminapthone for the preparation of a medicament .
  • aminapthone for the treatment of arteriophaties; preferably, • of all those types of arteriophaties referable to an inflammatory state of the arterial vasal structure; more preferably, of the endothelium.
  • said medicament could result suitable for the therapeutic treatment of: arteriosclerosis, atherosclerosis, obliterative arteriopathy, Raynaud disease secondary to connectivitis, primitive and secondary pulmonary hypertension, diabetic microangiopathy, Buerger's disease, systemic sclerosis and in all diseases characterized by endothelial damage and activation and consequent tissue ischemia.
  • the preparation of the medicament of the present invention is carried out in ' a traditional way by using, depending on the type of formulation that one wishes to prepare, " preparative techniques known to the skilled in the pharmaceutical sector.
  • Said preparation includes at least a step in which a therapeutically effective dose of active substance aminapthone, subject of the present invention, is additioned with a quantity of proper additives and excipients selected from: carriers, buffering agents, lubricants, dispers- ants, flavourings, sweeteners, stabilizers, preservatives, antioxidants commonly used in the pharmaceutical formulation technique.
  • starch starch
  • tween flavours, such as those of mandarin, grapefruit, strawberry, bilberry, all fruits, sucrose, glucose, acesulfame, saccharin, aspartame, ascorbic acid, parabens, glutamine, arginine, superoxide dismutase, glutathione.
  • Said medicament can be administered to patients by different administration routes.
  • a particularly preferred medicament of the present invention is formu- lated for oral administration.
  • compositions for oral administration are, for example, in form of capsules, beads, solutions or suspensions ready to drink, powders or granulates in sachets (to be suspended or dissolved in water or non- carbonated and non-alcoholic beverages at the time of use) or similar forms, tablets, effervescent formulations .
  • the medicament of the present invention can also be formulated in a coated, lacquered, encapsulated or microencapsulated form, so as to result gastroresis- tant.
  • Said medicament can also be formulated as a con- trolled-release form, so as to selectively release the active substances in the intestinal tract, particularly the colon.
  • parenteral or transdermic administration can be foreseen.
  • said medicament contains the active substance aminaphtone in a quantity between 30 and 150 mg/dose; preferably, from 50 to 100 mg/dose.
  • Said medicament is usually administered to the patient at a dosage between, on average, 75 and 450 mg/die; preferably, from 50 to 300 mg/die; more preferably, from 75 to 225 mg/die.
  • the medicament of the present invention including aminaphtone, has pointed out a direct protective effect of the arterial vascular endothelium through the block of cell and transcriptional mechanisms which are involved in the endothelial damage.
  • IL-i ⁇ represents a molecule also produced by humans in inflammation conditions and it is responsible for that series of alterations falling within the context of acute stage answers to stimuli .
  • ECV 304 cells are a human cell line presenting many- features of endothelial cells and is commonly used for studying, in a standardized way, cell functions thereof .
  • E-selectine expression covers an important role in arterial vascular pathologies by promoting the adhesion of platelets and the adhesion and the migration of inflammatory cells.
  • endothelin-1 production has been analyzed as it is fundamental in vasoconstriction and vascular remodelling processes typical of the endothelial injury.
  • Endothelin-1 is in fact mentioned as one of the determining pathogenic principles of several human pathologies, for example: primitive and secondary pulmonary hypertension, secondary Raynaud disease, inflammatory arteriopathies and atherosclerosis; it further promotes the hypertro- phic cardiomiopathy and the increase of the arterial pressure.
  • Cell lines ECV 304 they are cells coming from umbilical cord of a female Japanese new-born and spontane- ously immortalized at the 136 th step (distributed from Collection of Cell Cultures) . Such cells were cultured in a complete medium consisted of: Medium 199, L- glutamine 1%, penicillin/streptomycin 1% (Invitrogen) with an addition of 10% FCS (fetal calf serum) (Hy- clone) .
  • FCS fetal calf serum
  • Cells of the ECV304 line cultured in 28 cm 2 Petri dishes, were stimulated with IL-l ⁇ at 100 U/ml (Roche) over 48 hrs in a complete medium and complete medium additioned with aminaphtone at the concentration of 2; 4; 5 ⁇ g/ml, ' respectively.
  • concentrations are equivalent to concentrations reached "in vivo" through administration of Capillarema per os at the standard dosage of 3 capsules/day (capsules with 75 mg of active substance per day) .
  • cells untreated with IL-l ⁇ were incubated in a complete medium additioned with aminaphtone alone at the concentration of 4 ⁇ g/ml .
  • EIA-kit - Supernatants of cell samples ECV304 were collected, cultured as above, treated with IL-l ⁇ at 100 U/ml over 6-12-24 and 36 hrs or with IL-l ⁇ at 100 U/ml additioned with aminaphtone at the concentration of 2; 4; 6 ⁇ g/ml , respectively.
  • samples non- stimulated with IL-l ⁇ were incubated with the addition of aminaphtone alone at 2 ; 4 ; 6 ⁇ g/ml .
  • the concentration of ET-I existing in the supernatants was quantified through Endothelin-1 EIA-Kit (CAYMAN Chemical) in an interval between 0 and 250 pg/ml .
  • This immunometric test is based on the "sandwich” technique with a double antibody.
  • PPET- 1 Real-Time RT-PCR specific for Pre-Pro-ET-1 (PPET- 1) .
  • PPET-I gene was detected at 6- 12-24-36 hrs, respectively, in samples: treated with IL-l ⁇ (100 U/ml) ; treated with IL-l ⁇ (100 U/ml) additioned with aminaphtone (2; 4; 6 ⁇ h/ml) ; non-stimulated by IL-l ⁇ but treated with aminaphtone alone.
  • RT-PCR technique 'based on TaqMan technology was used (Applied Biosystems, Foster City, CA) , through a sequence determination system ABI PRISM 7000 (Applied Biosystems) . 2-4 ⁇ l were collected form each cDNA, diluted 1:5, in a final volume of 25 ⁇ l .
  • PCR mix containing ' Ix TaqMan Universal PCR Master Mix with Ampo- Erase UNG enzyme; a specific primer and a probe FAM- labelled mix (Assay-On-Demand Gene Expression Products; Applied Biosystems) .
  • AmpliTaq Gold enzyme was activated over 10 min. at 95 0 C. All genes were then amplified: a first step of 15 sec. At 95°C; a second step of 1 min. at 60 0 C; all for 50 total cycles.
  • the quantification of the specific mRNA PPET-I was normalized for the constitutive gene expression glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) .
  • GPDH glyceraldehyde-3-phosphate-dehydrogenase
  • CT comparative method CT
  • the CT value was defined as the number of PCR cycles required for overcome the fluorescence signal (defined as 10-fold the standard deviation of the basal variation) .
  • the ⁇ CT value was defined as the difference between CT of mRNA PPET-I and CT of mRNA GAPDH. The course of the mRNA PPET expression was computed according to the formula 2-
  • ⁇ CT results to be the difference between each ⁇ CT and the ⁇ CT of the sample having the lowest mRNA (calibrator) .
  • aminapthone is capable of reducing in a statistically significant way the E-selectine expression (ELAM-I) in ECV304 cells (MC: mean ⁇ standard deviation: 219 ⁇ 8.3; % positive cells 19.4 ⁇ 1.7) relative to cells incubated with the complete culture medium alone (MC: mean ⁇ standard deviation: 250 + 22 p ⁇ 0.05; % positive cells 29.1 ⁇ 3.1; p ⁇ 0.05).
  • aminapthone inhibits " , with a dose-dependent course, the expression of adhesive molecules in activated cells; (cells incubated with IL-l ⁇ 100 U/ml : MC: mean + standard deviation: 369.6 ⁇ 30.5; % positive cells: 38.4 ' + 3.7); (cells incubated with IL-l ⁇ 100 U/ml.
  • EIA-kit confirms the trend, already observed at a level of gene transcription of PRE-PRO-ET-I, according to which aminapthone tends to reduce the ET-I production from samples of ECV304 cells, both stimulated with IL-I and incubated with the culture medium alone. Furthermore, it has been noted that such inhibition on ET-I production resulted confirmed in all times and had a dose-dependent course. (Fig. 2 and 3) . The trend to a linear decrement of the ET-I concentration in different times with increasing concentrations of aminapthone has reached a statistical significance in the following cases :
  • basal medium vs . aminapthone 4 mcg/ml p ⁇ 0.05
  • basal medium vs. aminapthone 6 mcg/ml p ⁇ 0.05

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Emergency Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Epidemiology (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Endocrinology (AREA)
  • Vascular Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Neurology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP07734240A 2006-04-11 2007-04-10 Utilisation d'aminaphtone pour la préparation d'un médicament destiné au traitement d'artériopathies Active EP2004173B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP11153882.3A EP2335695B1 (fr) 2006-04-11 2007-04-10 Utilisation d'aminaphtone pour la préparation d'un médicament destiné au traitement d'artériopathies

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT000712A ITMI20060712A1 (it) 2006-04-11 2006-04-11 Uso di aminaftone per la preparazione di un medicamento per il trattamento delle arteriopatie
PCT/IB2007/000921 WO2007116297A2 (fr) 2006-04-11 2007-04-10 Utilisation d'aminaphtone pour la préparation d'un médicament destiné au traitement d'artériopathies

Related Child Applications (2)

Application Number Title Priority Date Filing Date
EP11153882.3A Division EP2335695B1 (fr) 2006-04-11 2007-04-10 Utilisation d'aminaphtone pour la préparation d'un médicament destiné au traitement d'artériopathies
EP11153882.3 Division-Into 2011-02-09

Publications (2)

Publication Number Publication Date
EP2004173A2 true EP2004173A2 (fr) 2008-12-24
EP2004173B1 EP2004173B1 (fr) 2011-10-12

Family

ID=38480588

Family Applications (2)

Application Number Title Priority Date Filing Date
EP07734240A Active EP2004173B1 (fr) 2006-04-11 2007-04-10 Utilisation d'aminaphtone pour la préparation d'un médicament destiné au traitement d'artériopathies
EP11153882.3A Active EP2335695B1 (fr) 2006-04-11 2007-04-10 Utilisation d'aminaphtone pour la préparation d'un médicament destiné au traitement d'artériopathies

Family Applications After (1)

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EP11153882.3A Active EP2335695B1 (fr) 2006-04-11 2007-04-10 Utilisation d'aminaphtone pour la préparation d'un médicament destiné au traitement d'artériopathies

Country Status (10)

Country Link
US (2) US8202903B2 (fr)
EP (2) EP2004173B1 (fr)
JP (1) JP2009533414A (fr)
AT (1) ATE527997T1 (fr)
BR (1) BRPI0711841A2 (fr)
CA (1) CA2648751C (fr)
ES (2) ES2519345T3 (fr)
IT (1) ITMI20060712A1 (fr)
PT (2) PT2335695E (fr)
WO (1) WO2007116297A2 (fr)

Families Citing this family (3)

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Publication number Priority date Publication date Assignee Title
IT1400389B1 (it) * 2010-05-27 2013-05-31 Baldacci Lab Spa Aminaftone per uso nel trattamento e/o nella prevenzione dell'emicrania
US9753909B2 (en) 2012-09-07 2017-09-05 Splunk, Inc. Advanced field extractor with multiple positive examples
US9152929B2 (en) 2013-01-23 2015-10-06 Splunk Inc. Real time display of statistics and values for selected regular expressions

Family Cites Families (10)

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Publication number Priority date Publication date Assignee Title
AT252224B (de) * 1964-10-05 1967-02-10 Finanz Kompensations Anst Verfahren zur Herstellung von neuen 2-Aminobenzoyloxy-naphthohydrochinonen
ES456574A1 (es) * 1977-03-07 1978-02-16 Rocador Sa Procedimiento de obtencion de pentametil-carbamato de quer- cetina.
IT1201149B (it) * 1987-01-14 1989-01-27 Indena Spa Complessi di bioflavonoidi con fosfolipidi,loro preparazione,uso e composizioni farmaceutici e cosmetiche
US5648377A (en) * 1993-12-21 1997-07-15 Indena S.P.A. Formulations containing carotenoids an procarotenoids combined with polyphenols in the prevention of the damages due to an abnormal production of free radicals
IT1275955B1 (it) * 1995-03-22 1997-10-24 Dompe Spa Formulazioni farmaceutiche in forma di gel tissotropico
DK1317272T3 (da) * 2000-05-25 2006-08-14 Boehringer Ingelheim Int Middel til forbedret cellebeskyttelse omfattende en lipofil antioxidant og en hydrofil antioxidant
JP2003238439A (ja) * 2002-02-13 2003-08-27 Yasuhiko Tabata 虚血治療剤
AU2003235931A1 (en) * 2002-05-13 2003-11-11 Takata Seiyaku Co., Ltd. Vintoperol-containing medicinal composition for transdermal administration
US7202222B2 (en) * 2003-01-06 2007-04-10 National Bioscience Corporation Methods for treatment of obesity and effective fat loss promotion
JP4598593B2 (ja) * 2004-05-10 2010-12-15 晶岩 韓 虚血再灌流による微小循環障害の予防・治療用薬剤

Non-Patent Citations (1)

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Title
See references of WO2007116297A2 *

Also Published As

Publication number Publication date
EP2004173B1 (fr) 2011-10-12
WO2007116297A2 (fr) 2007-10-18
PT2004173E (pt) 2012-01-11
CA2648751C (fr) 2013-01-22
PT2335695E (pt) 2014-10-29
EP2335695A1 (fr) 2011-06-22
US20120022155A1 (en) 2012-01-26
EP2335695B1 (fr) 2014-08-20
US20090182045A1 (en) 2009-07-16
ITMI20060712A1 (it) 2007-10-12
ES2519345T3 (es) 2014-11-06
ATE527997T1 (de) 2011-10-15
ES2374659T3 (es) 2012-02-20
CA2648751A1 (fr) 2007-10-18
WO2007116297A3 (fr) 2008-01-10
US8202903B2 (en) 2012-06-19
US10028929B2 (en) 2018-07-24
BRPI0711841A2 (pt) 2011-12-13
JP2009533414A (ja) 2009-09-17

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